Chemotherapy-induced adverse effects (CIAE) including peripheral neuropathy and cardiovascular adverse effects, among others, are painful and often irreversible side-effects of treatment that affects many cancer patients who undergo chemotherapy. CIAE interferes with a patient's daily living and impairs quality of life. More importantly, CIAE is a concern because these adverse effects can result in chemotherapy dose reductions and discontinuation of treatment. The cellular mechanisms responsible for CIAE are unknown and there is no standard treatment for the prevention or management of CIAE, including chemotherapy induced calcium signaling disregulation, neuropathy/peripheral neuropathy (CIN/CIPN) and chemotherapy induced cardiovascular adverse effects (CICAE), among other adverse effects.
For example, paclitaxel (Taxol®) is the most effective drug for treating breast and ovarian cancer. A major side-effect of treatment with paclitaxel is peripheral neuropathy. Approximately thirty percent of the women treated with paclitaxel are affected by irreversible CIPN and suffer discomfort and pain. To date, elucidating the cellular mechanisms through which paclitaxel and several other commonly used anti-cancer drugs including vincristine cause CIAE, including CIN/CIPN and/or CICAE has proven difficult and many paclitaxel (Taxol®) treated patients are at risk of discontinuing potentially life-extending treatments because of their inability to tolerate CIAE.
Patients treated with paclitaxel have been shown to develop arrhythmias and cardiac dysfunction (chemotherapy induced cardiovascular adverse effects or CICAE) that has been linked to dysregulated calcium signaling. See for example, Yeh, et al., Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. Journal of the American College of Cardiology 53, 2231-2247 (2009) and Zhang, et al., Paclitaxel accelerates spontaneous calcium oscillations in cardiomyocytes by interacting with NCS-1 and the InsP3R. Journal of molecular and cellular cardiology 49, 829-835 (2010). Cardiomyocytes isolated from mice treated with paclitaxel show an increase in the frequency of spontaneous calcium oscillations. These changes in cardiomyocytes result from the increased interaction of NCS-1 with the InsP3R31.
Thus, strategies are needed to prevent unwanted CIAE-related related adverse effects of chemotherapy, including calcium signaling disregulation, CIN/CIPN and/or CICAE without altering the ability to treat the cancer. The need exists for methods of treatment that alleviate the peripheral neuropathy that is often suffered by patients who undergo treatment with one or more anti-cancer drugs such as paclitaxel (Taxol®).